Acquired Immunodeficiency Syndrome (AIDS) is a fatal disease of the immune system transmitted through blood especially by sexual contact or contaminated needles and is presumed to be caused by the HIV virus, which is an RNA genetically unique retrovirus, having a gene not found to date in other retroviruses.
One of the many drugs found to be active against HIV virus is efavirenz of formula (I), chemically known as (−)-6-Chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3.1-benzoxazin-2-one. Efavirenz marketed as Sustiva is clinically active specifically against human immunodeficiency virus type 1 (HIV-1) and is a non-nucleoside, reverse transcriptase inhibitor. The activity of Efavirenz is mediated predominantly by non-competitive inhibition of HIV-1 RT without affecting HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta.

U.S. Pat. No. 5,519,021 (assigned to Merck) discloses a method in which efavirenz (I) is obtained by reaction of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol of formula (II) with a large excess of carbonyl diimidazole of formula (III) for obtaining the oxazinone ring.

The reaction utilizes dry tetrahydrofuran as solvent and which has a tendency to develop peroxides during storage. In order to obtain dry tetrahydrofuran free of peroxides, purification and drying agents are required, and such process of purification and drying adds on to the cost. As reported in the widely accepted literature, Textbook of Practical Organic Chemistry—Vogel; 5th Edition, page 406-407 discloses use of solid potassium hydroxide followed by refluxing over calcium hydride or lithium aluminium hydride for drying tetrahydrofuran, which is not advisable on a commercial scale due to the fire catching tendency and explosive nature of the metallic hydrides. Also, the related note draws attention towards the hazards of drying with respect to peroxides during purification. Further, the volume of tetrahydrofuran utilized is also about 16 times of starting material, which is quite exorbitant for commercial use.
The reaction is carried out at 55° C. and takes about 24 hours for completion. Also, the work up of the reaction involving distillation of tetrahydrofuran is quite risky and dangerous due to the potential of tetrahydrofuran to develop peroxides. The residue obtained after concentration is redissolved in ethyl acetate and partitioned with water followed by re-extraction with ethyl acetate. The process also has an elaborate work up method requiring aqueous washings with dilute acid, alkaline solution and brine followed by separation of organic layer, drying over a drying agent and subsequent distillations, which consumes lot of time and utility. Moreover during such washings, there is a potential danger for formation of emulsion. This lowers the yield as in the case of U.S. Pat. No. 5,519,021 to about 85%, thereby making the process unsuitable for commercial purpose.
Therefore, U.S. Pat. No. 5,519,021 suffers from various shortcomings such as:                1) Risk of using tetrahydrofuran, which is known to have an explosive nature due to its tendency to develop peroxides on storage,        2) Requirement of stringent anhydrous conditions as dry tetrahydrofuran is employed as solvent for the reaction,        3) Large volume of tetrahydrofuran is required,        4) Long reaction time reduces the efficiency of the reaction and also increases the reactor occupancy,        5) Repeated washings with aqueous solvent such as dilute acid, alkaline solution and brine increases the load on the effluent treatment plant,        6) Tendency to form emulsion during alkaline work up reduces the yield.        
U.S. Pat. No. 5,633,405 (assigned to Merck) discloses another process for obtaining an efavirenz derivative of formula (VI) by reaction of the amino alcohol of formula (IV) with phosgene utilizing a mixture of toluene and tetrahydrofuran as solvent and triethyl amine as a base. The use of tetrahydrofuran as already mentioned requires an additional step of purification for removal of peroxides.
Product isolation involves quenching with cold water, followed by extraction with yet another solvent like ethyl acetate. Based on the example, demulsification is carried out with saturated brine solution. Breaking of an emulsion generally takes long time and this affects the time cycle, reactor occupancy etc. Further washings of the organic layer are carried out with citric acid solution followed by brine solution. The organic layer thus obtained is dried over sodium sulphate and concentrated to give brown oil, which is then recrystallized from a 5:1 mixture of hexane:ethyl acetate to give the compound of formula (VI) in 85% yield.

There is an additional step of deprotection of the nitrogen atom in the oxazinone ring of the compound of formula (VI) with a reagent like ceric ammonium nitrate to give efavirenz, which was isolated by column chromatography.
The process has the following disadvantages:                1) Reaction is carried out with a binary solvent mixture of toluene and tetrahydrofuran. Further, a third solvent like ethyl acetate is required for extraction to give the crude product. Also, a fourth solvent like hexane in combination with ethyl acetate is employed for purification of the product of formula (VI). Utilization of four different solvents leads to manifold increase in cost, raises the inventory of solvents and further also increases the load on the effluent due to the use of a water-miscible solvent like tetrahydrofuran.        2) The specification itself acknowledges that emulsification is an inherent part of the process. Isolation of any product from an emulsion is quite tedious and cumbersome on an industrial scale, leading to loss in yield.        3) The product obtained after such a laborious work-up requires purification by recrystallization.        4) Utilization of ceric ammonium nitrate in the final deprotection step to give efavirenz (I) generates an enormous load on effluent treatment as it is quite difficult to remove the heavy metal on a commercial scale. In short, the whole process is quite long, thereby reducing the overall efficiency of the process.        
This process has also been disclosed in Journal of Organic Chemistry 1998, 63, 8536-8543 and Tetrahedron Letters 1995, 36, 8937-8940.
U.S. Pat. No. 5,932,726 (assigned to DuPont) discloses a process for the preparation of efavirenz of formula (I) by reaction of the efavirenz intermediate (II) with phosgene in a solvent such as heptane, toluene and tetrahydrofuran or mixtures thereof. The preferred solvent is a mixture of heptane and tetrahydrofuran. During the reaction, a third solvent like methanol is added. After the reaction heptane is added and the mixture partially concentrated. A mixture of heptane and tetrahydrofuran is added and the resulting mixture washed with aqueous sodium bicarbonate solution followed by water. The mixture was warmed to 50° C. and diluted with heptane to obtain the product.

The drawbacks of the process are:                1) Process requires three solvents, namely heptane, tetrahydrofuran and methanol, Out of these 3 solvents, tetrahydrofuran (65° C.) and methanol (65° C.), have identical boiling points, therefore recovery of these solvents in a pure form is quite difficult. Both these solvents are water-soluble; hence recovery of these solvents based on their water solubility also is not possible,        2) The total volume of the solvents required for the reaction and before isolation is about 12 times the batch size. Isolation of the product requires an additional 9.0 times volume of a mixture of heptane and tetrahydrofuran. Therefore, the total volume required is about 21 times the batch size, which is quite high for reactions to be carried out on a large scale, leading to considerable cost escalation.        3) work-up involves distillation of tetrahydrofuran, which is very dangerous due to its explosive nature associated with peroxide formation during storage,        4) work up involves washing with dilute alkali solution wherein there is a tendency for emulsification, which is quiet tedious to remove on a commercial scale. Emulsification reduces the yield and demulsification consumes lot of time and energy on a large scale,        
Therefore, the process disclosed in U.S. Pat. No. 5,932,726 is quite costly and not feasible due to the large amount of solvents, and is also lengthy, laborious, cumbersome for industrial scale.
Synthesis 2000, 4, 479-495 and Journal of Organic Chemistry 1998, 63(23) 8536-8543 also discloses a similar process for the preparation of the benzoxazinone ring for the preparation of efavirenz of formula (I).
U.S. Pat. No. 6,147,210 (assigned to DuPont Pharmaceuticals) discloses a process in which the desired benzoxazinone ring was obtained comprising reaction of compound of formula (VII) in toluene/hexane mixture utilizing n-butyl lithium as base. The reaction was refluxed for 4 hours for completion of reaction. The product was isolated by quenching with a mixture of 5% acetic acid and t-butyl methyl ether. The organic layer was separated, washed twice with sodium chloride solution and concentrated to get a residue from which the product was isolated by addition of heptane.

This process has the following drawbacks:                1) The reaction requires about 5.5 times of a solvent mixture of toluene and acetonitrile followed by 5 times volume the batch size each of 5% acetic acid solution and methyl t-butyl ether. Also, an additional 5 times of a third solvent like heptane is added during isolation of the product. Thus, the total volume of solvent required is about 20 times the batch size, which reduces the batch size, increases the time cycle for each batch run and reduces the efficiency of the process.        2) Utilization of four solvents such as toluene, hexane, methyl tert-butyl ether and heptane increases the inventory of solvents. Further, the use of methyl tert-butyl ether as a solvent finds limited use due to environmental and health concerns as it easily pollutes ground water. Successive washings with sodium chloride solution during isolation of compound of formula (I) suggests that there is a distinct possibility of emulsion formation during work up. All these shortcomings dissuade the use of the above disclosed process for preparation of efavirenz on an industrial scale.        
Synthetic Communications 27(24), 4373-4384 (1997) also reports a similar process.
U.S. Pat. No. 6,015,926 (assigned to Merck & Co) discloses a process for the preparation of efavirenz by reaction of amino alcohol of formula (II) with phosgene utilizing methyl tert-butyl ether or toluene as solvent and aqueous potassium bicarbonate solution. After the reaction, the organic layer is separated and after brine washing the organic layer is concentrated. Efavirenz of formula (I) is isolated after the addition of ethanol or isopropanol to the residue. The crude efavirenz thus obtained is recrystallized from a mixture of isopropanol and water.

Use of methyl tert-butyl ether is generally not preferred on a commercial scale due to environmental hazards and health concerns. Further, the reaction and isolation of efavirenz (I) requires solvents such as                i) toluene or methyl tert-butyl ether during reaction,        ii) ethanol or isopropanol during isolation and        iii) mixture of isopropanol and water during recrystallization of efavirenz (I).        
The requirement of multiple solvents increases the inventory and increase the process cost considerably.
U.S. Pat. No. 6,114,569 (assigned to Merck) discloses a process in which the benzoxazinone ring is formed by reaction of the carbamate derivative of an efavirenz intermediate of formula (VIII) in the presence of an aqueous solution of a base utilizing a solvent from the group selected from methyl t-butyl ether, toluene, tetrahydrofuran, acetonitrile, dimethyl acetamide, N-methylpyrrolidinone or mixtures thereof.

The reaction utilizes a high amount of solvent like tetrahydrofuran, up to 14 times the batch size for the reaction. After the reaction the mixture is quenched with an aqueous solution of a base (21 times), followed by addition of a second solvent like methyl tert-butyl ether (14 times). After the alkaline treatment, the organic layer was concentrated and the residue diluted with ethanol or isopropanol for isolation of the impure product of formula (I), which is then recrystallized from a high dilution (about 110 times) of an aqueous solution of isopropanol or ethanol.
This process although not utilizing phosgene for the preparation of the benzoxazinone ring has the following disadvantages:                i) requires a solvent dilution of up to 14 times of the batch size during the reaction. Quenching is done with an additional 21 times batch size of an aqueous solution of an inorganic base. A second solvent such as methyl tert-butyl ether is added up to 14 times dilution. This raises the total volume to about 50 times, which is highly exorbitant on a commercial scale. Such high volumes drastically reduces the batch size,        ii) Distillation of such high volume of solvent during isolation increases the time cycle for each batch run, consumes enormous amount of time, energy such that the efficiency of the process gets phenomenally reduced,        iii) The compound of formula (I) thus isolated with enormously high dilution of solvent requires an additional recrystallization thus introducing an additional step of purification and also raises the cost tremendously.        
Based on the foregoing, it is evident that prior art has the following drawbacks:                1) Requires anhydrous reaction condition. Further, utilization of solvents like tetrahydrofuran, which are prone to develop peroxides on storage, requires solvent purification for removing the peroxides.        2) Requires high dilution of solvents, which reduces the batch size, increases the distillation time, eventually increasing the time cycle for each run, thereby reducing the efficiency of the process.        3) Utilization of multiple solvents for obtaining compound of formula (I) increases the solvent inventory reduces the possibility of obtaining a pure solvent for reuse when boiling points are close. Use of multiple solvents also increases the process cost considerably.        4) Emulsion formation during work up significantly reduces the yield or requires enormous time for de-emulsification.        5) Efavirenz of formula (I) isolated after the cyclization requires an additional step of purification for obtaining the desired form of the product.        6) Utilization of a reagent like ceric ammonium nitrate for deprotection of the nitrogen atom in the oxazinone ring drastically increases the load on the effluent treatment due to heavy metal contamination.        